Single nucleotide polymorphisms in DNA repair genes as risk factors associated to prostate cancer progression.

BACKGROUND: Besides serum levels of PSA, there is a lack of prostate cancer specific biomarkers. It is need to develop new biological markers associated with the tumor behavior which would be valuable to better individualize treatment. The aim of this study was to elucidate the relationship between single nucleotide polymorphisms (SNPs) in genes involved in DNA repair and prostate cancer progression. METHODS: A total of 494 prostate cancer patients from a Spanish multicenter study were genotyped for 10 SNPs in XRCC1, ERCC2, ERCC1, LIG4, ATM and TP53 genes. The SNP genotyping was made in a Biotrove OpenArray® NT Cycler. Clinical tumor stage, diagnostic PSA serum levels, and Gleason score at diagnosis were obtained for all participants. Genotypic and allelic frequencies were determined using the web-based environment SNPator. RESULTS: SNPs rs11615 (ERCC1) and rs17503908 (ATM) appeared as risk factors for prostate cancer aggressiveness. Patients wild homozygous for these SNPs (AA and TT, respectively) were at higher risk for developing cT2b - cT4 (OR = 2.21 (confidence interval (CI) 95% 1.47 - 3.31), p < 0.001) and Gleason scores ≥ 7 (OR = 2.22 (CI 95% 1.38 - 3.57), p < 0.001), respectively. Moreover, those patients wild homozygous for both SNPs had the greatest risk of presenting D'Amico high-risk tumors (OR = 2.57 (CI 95% 1.28 - 5.16)). CONCLUSIONS: Genetic variants at DNA repair genes are associated with prostate cancer progression, and would be taken into account when assessing the malignancy of prostate cancer.

International radiation oncology trainee decision making in the management of radiotherapy-induced nausea and vomiting.

PURPOSE: This study explored international radiation oncology trainee decision making in the management of radiotherapy-induced nausea and vomiting (RINV). METHODS: Radiation oncology trainees who were members of the national radiation oncology associations of the USA, Canada, Netherlands, Australia, New Zealand, France, Spain and Singapore completed a Web-based survey. Respondents estimated the risks of nausea and vomiting associated with six standardised radiotherapy-only clinical case vignettes modelled after international anti-emetic guidelines and then committed to prophylactic, rescue or no therapy as an initial management approach for each case. RESULTS: One hundred and seventy-six trainees from 11 countries responded. Only 28 % were aware of any anti-emetic guideline. In general, risk estimates and management approaches for the high-risk and minimal risk cases varied less and were more in line with guideline standards than were estimates and approaches for the moderate- and low-risk cases. Prophylactic therapy was the most common approach for the high-risk and a moderate-risk case (83 and 71 % of respondents respectively), while rescue therapy was the most common approach for a second moderate-risk case (69 %), two low-risk cases (69 and 76 %) and a minimal risk case (68 %). A serotonin receptor antagonist was the most commonly recommended prophylactic agent. On multivariate analysis, a higher estimated risk of nausea predicted for recommending prophylactic therapy, and a lower estimated risk of nausea predicted for recommending rescue therapy. CONCLUSIONS: Radiation oncology trainee risk estimates and recommended management approaches for RINV clinical case vignettes varied and matched guideline standards more often for high-risk and minimal risk cases than for moderate- and low-risk cases. Risk estimates of nausea specifically were strong predictors of management decisions.

Determination of the optimal range for virtual monoenergetic images in dual-energy CT based on physical quality parameters.

PURPOSE: Virtual monoenergetic images (VMI) obtained from Dual-Energy Computed Tomography (DECT) with iodinated contrast are used in radiotherapy of the Head and Neck to improve the delineation of target volumes and organs at-risk (OAR). The energies used to vary from 40 to 70 keV, but noise at low keV and the use of Single Energy CT (SECT) at low kVp settings may shrink this interval. There is no guide about how to find out the optimal range where VMI has a significant improvement related to SECT images. Our study proposes a procedure to determine this optimal range, based on common image quality parameters, and establishes this range in a Siemens Somatom Confidence and a Head and Neck protocol. METHODS: We compared the quality of the VMI series at 40-60 keV versus single X-ray tube voltage computed tomography (SECT) at 80 and 120 kVp . Our reference was 120 kVp . DECT images were sequentially acquired using the Siemens Somatom Confidence RT Pro CT according to the head and neck protocol in our department. VMI series were constructed using the Syngo Via software Monoenergetic+ algorithm. Quality parameters were: image uniformity, high- and low-contrast resolution, noise, and sensitivity to the iodinated contrast. We used the Catphan 604 phantom for quality control, except when assessing iodine sensitivity. To evaluate high contrast resolution, we calculated the modulation transfer function (MTF) using the point spread function estimation of a point bead and the slanted edge methods. For the low-contrast resolution, we used a statistical method for assessing differences between contrast structures and local noise. To measure the absolute value of noise and compare its texture, we used the standard deviation and the noise power spectrum. We measured iodine sensitivity by dissolving the Optiray Ultraject iodinated contrast in water in concentrations of 0 to 4500 mg/l and then compared the contrast to noise ratio (CNR) and analyzed the linear correlation between concentration and HU. RESULTS: The entire series met the minimum quality requirements. However, the one at 40 keV presented uniformity at the limits of acceptability. The high- and low-contrast resolutions were similar between series. The noise of the VMI series decreased with increasing energy, while sensitivity to the contrast displayed the opposite behavior. All series showed linearity of HUs from very low iodine concentrations. Images at 60 keV presented lower iodine sensitivity than SECT at 80 kVp , while those at 55 keV were similar to them. CONCLUSIONS: Our method of image comparison based on standard quality parameters in phantom gave clear results about the optimal range and can be used as a guide to characterize any other DECT imaging protocols. The optimal range for using VMI images in iodinated contrasts in the Siemens system was 45-55 keV. Lower energies lacked noise and uniformity, while higher ones could be substituted by SECT images at low kilovoltage (80 kVp ).

Custom 3D-printed applicators for high dose-rate brachytherapy in skin cancer.

PURPOSE: This paper describes the protocol for the development of 3D-printed custom applicators in treating skin carcinoma, the evaluation of the materials used, and the methods for segmentation and rendering of the applicators. MATERIAL AND METHODS: The segmentation and rendering process for the applicator had six phases: (i) determination of the volume of the lesion using a computed tomography (CT) scan; (ii) delineation of the patient surface, using the same CT images; (iii) creation of the applicator in the planner and segmentation of the mold; (iv) preliminary dosimetry and establishment of the route of the catheter from the brachytherapy unit; (v) creation of the 3D applicator using specialized software; and (vi) applicator printing. Following this process, the patient returned for a second CT to undergo the definitive dosimetry with the applicator in place. Radiation therapy was then administered. RESULTS: We made a total of 16 applicators. Only three applicators had to be remade, two due to an error in the infill and the other due to incorrect catheter geometry. In all cases, correct coverage of the planning target volume was achieved with the prescribed isodose. CONCLUSIONS: The creation of custom molds in plesiotherapy for skin cancer with 3D printing is feasible. Compared to manual methods, 3D printing increases precision in applicator geometry and optimization of the dosimetry.

Randomized clinical trial with two palliative radiotherapy regimens in painful bone metastases: 30 Gy in 10 fractions compared with 8 Gy in single fraction.

BACKGROUND AND PURPOSE: The aim was to demonstrate similar pain relief with two schedules of radiotherapy for painful bone metastases. MATERIALS AND METHODS: A total of 160 patients were assigned to receive a single 8-Gy fraction or 30 Gy in 10 fractions. Pain intensity was measured on an ordinal pain scale of 0-10. Partial response was defined as a pain reduction of two points or more and complete response as a pain score of zero at the treated area. Response follow-up was at 3, 12, 24 and 48 weeks. RESULTS: The overall response was 75% in the 8-Gy arm and 86% in the 30-Gy arm. Complete response and partial response rates were 15% and 60% in the 8-Gy arm, 13% and 73% in the 30-Gy arm. Acute toxicity was of 18% in the 30-Gy arm and of 12% in the 8-Gy arm. These differences were not statistically significant. The re-treatment rate was 28% vs 2% in the 8-Gy and 30-Gy arms, respectively, these were statistically significant. CONCLUSIONS: A single-fraction regimen of 8 Gy was as safe and effective as a multifraction regimen of 30 Gy for painful bone metastases in terms of pain relief.

Breast metastases from a floor of the mouth carcinoma.

Metastases to the breast from extramammary tumours are uncommon and metastatis of floor of the mouth carcinoma to the breast is extremely rare. The clinical outcome of these patients remains dismal. We report the case of breast metastases from a floor of the mouth carcinoma successfully treated by conservative surgery and adjuvant radiotherapy with no demonstrable metastases 33 months after the initial diagnosis.

Genetic variations in genes involved in testosterone metabolism are associated with prostate cancer progression: A Spanish multicenter study.

BACKGROUND: Prostate cancer (PCa) is an androgen-dependent disease. Nonetheless, the role of single nucleotide polymorphisms (SNPs) in genes encoding androgen metabolism remains an unexplored area. PURPOSE: To investigate the role of germline variations in cytochrome P450 17A1 (CYP17A1) and steroid-5α-reductase, α-polypeptides 1 and 2 (SRD5A1 and SRD5A2) genes in PCa. PATIENTS AND METHODS: In total, 494 consecutive Spanish patients diagnosed with nonmetastatic localized PCa were included in this multicenter study and were genotyped for 32 SNPs in SRD5A1, SRD5A2, and CYP17A1 genes using a Biotrove OpenArray NT Cycler. Clinical data were available. Genotypic and allelic frequencies, as well as haplotype analyses, were determined using the web-based environment SNPator. All additional statistical analyses comparing clinical data and SNPs were performed using PASW Statistics 15. RESULTS: The call rate obtained (determined as the percentage of successful determinations) was 97.3% of detection. A total of 2 SNPs in SRD5A1-rs3822430 and rs1691053-were associated with prostate-specific antigen level at diagnosis. Moreover, G carriers for both SNPs were at higher risk of presenting initial prostate-specific antigen levels>20ng/ml (Exp(B) = 2.812, 95% CI: 1.397-5.657, P = 0.004) than those who are AA-AA carriers. Haplotype analyses showed that patients with PCa nonhomozygous for the haplotype GCTTGTAGTA were at an elevated risk of presenting bigger clinical tumor size (Exp(B) = 3.823, 95% CI: 1.280-11.416, P = 0.016), and higher Gleason score (Exp(B) = 2.808, 95% CI: 1.134-6.953, P = 0.026). CONCLUSIONS: SNPs in SRD5A1 seem to affect the clinical characteristics of Spanish patients with PCa.

Polymorphisms in DNA-repair genes in a cohort of prostate cancer patients from different areas in Spain: heterogeneity between populations as a confounding factor in association studies.

BACKGROUND: Differences in the distribution of genotypes between individuals of the same ethnicity are an important confounder factor commonly undervalued in typical association studies conducted in radiogenomics. OBJECTIVE: To evaluate the genotypic distribution of SNPs in a wide set of Spanish prostate cancer patients for determine the homogeneity of the population and to disclose potential bias. DESIGN SETTING AND PARTICIPANTS: A total of 601 prostate cancer patients from Andalusia, Basque Country, Canary and Catalonia were genotyped for 10 SNPs located in 6 different genes associated to DNA repair: XRCC1 (rs25487, rs25489, rs1799782), ERCC2 (rs13181), ERCC1 (rs11615), LIG4 (rs1805388, rs1805386), ATM (rs17503908, rs1800057) and P53 (rs1042522). The SNP genotyping was made in a Biotrove OpenArray® NT Cycler. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Comparisons of genotypic and allelic frequencies among populations, as well as haplotype analyses were determined using the web-based environment SNPator. Principal component analysis was made using the SnpMatrix and XSnpMatrix classes and methods implemented as an R package. Non-supervised hierarchical cluster of SNP was made using MultiExperiment Viewer. RESULTS AND LIMITATIONS: We observed that genotype distribution of 4 out 10 SNPs was statistically different among the studied populations, showing the greatest differences between Andalusia and Catalonia. These observations were confirmed in cluster analysis, principal component analysis and in the differential distribution of haplotypes among the populations. Because tumor characteristics have not been taken into account, it is possible that some polymorphisms may influence tumor characteristics in the same way that it may pose a risk factor for other disease characteristics. CONCLUSION: Differences in distribution of genotypes within different populations of the same ethnicity could be an important confounding factor responsible for the lack of validation of SNPs associated with radiation-induced toxicity, especially when extensive meta-analysis with subjects from different countries are carried out.

Neuroendocrine small cell carcinoma of the uterine cervix.

Neuroendocrine small cell carcinoma of the uterine cervix (SCC) is a rare disease that mixes clinical and biological characteristics of both cervical neoplasms and neuroendocrine small cell cancer. The prognosis is poor and the optimal treatment has not yet been clarified. Multimodality treatment, with surgery and concurrent chemoradiation has recently been shown to improve local control and survival rates.